SARS-CoV-2 infection triggers paracrine senescence and leads to a sustained senescence-associated inflammatory response

Abstract

Reports of post-acute COVID-19 syndrome, in which the inflammatory response persists even after SARS-CoV-2 has disappeared, are increasing1, but the underlying mechanisms of post-acute COVID-19 syndrome remain unknown. Here, we show that SARS-CoV-2-infected cells trigger senescence-like cell-cycle arrest2,3 in neighboring uninfected cells in a paracrine manner via virus-induced cytokine production. In cultured human cells or bronchial organoids, these SASR-CoV-2 infection-induced senescent cells express high levels of a series of inflammatory factors known as senescence-associated secretory phenotypes (SASPs)4 in a sustained manner, even after SARS-CoV-2 is no longer detectable. We also show that the expression of the senescence marker CDKN2A (refs. 5,6) and various SASP factor4 genes is increased in the pulmonary cells of patients with severe post-acute COVID-19 syndrome. Furthermore, we find that mice exposed to a mouse-adapted strain of SARS-CoV-2 exhibit prolonged signs of cellular senescence and SASP in the lung at 14 days after infection when the virus was undetectable, which could be substantially reduced by the administration of senolytic drugs7. The sustained infection-induced paracrine senescence described here may be involved in the long-term inflammation caused by SARS-CoV-2 infection.

Mucosal immune responses to infection and vaccination in the respiratory tract

“…It has also been found that IL17A and IFNγ concentrations were inversely related to age during an acute phase of SARS-CoV-2 infection, indicating a difference in the immune response in aged adults ( Pierce et al., 2020 ). Additionally, in the context of SARS-CoV-2, gene-expression markers of senescence ( CDKN2A and senescence-associated secretory phenotypes [SASP] factor genes) were upregulated in pulmonary cells in patients with severe COVID-19 ( Tsuji et al., 2022 ). In order to characterize and compare the lung-specific immune response to influenza and SARS-CoV-2 in aged individuals, another study utilized lung tissue from deceased donors 22–68 years old ( Nguyen et al., 2021 ).…”

SARS-CoV-2-induced senescence as a potential therapeutic target

“…They correlate their findings in vitro by demonstrating the establishment of senescence in Vero-E6 epithelial kidney cells infected with SARS-CoV-2, with dramatically reduced implementation of senescence in response to treatment with a selective ATM inhibitor, strongly suggesting DNA damage as an initiator of senescence in this setting. Interestingly, Tsuji et al recently proposed virus-induced cytokine production as an inducer of senescence in COVID-19 infections, having demonstrated that human lung diploid fibroblasts infected with SARS-CoV-2 can induce a senescent-like phenotype in neighbouring uninfected cells [ 16 ]. The senescent cells then continue to express high levels of SASP factors even once SARS-CoV-2 infection is no longer detectable, a finding corroborated by re-analysis of single-cell transcriptomic data from lung tissue of patients with severe and prolonged COVID-19 [ 17 ].…”

“…The work of Evangelou et al ., [ 2 ] and others [ 16 , 18 , 19 ] contribute towards answering these questions, providing a significant contribution to understanding the role of senescence in the cytokine storm and severe multi-organ morbidity that has characterised severe clinical forms of COVID-19.…”

Ageing impairs protective immunity and promotes susceptibility to murine visceral leishmaniasis

“…The immunosenescence induced by physiological processes or chronic infection has been associated with a significant increase in host susceptibility to infections (Gardner, 1980; Marston et al ., 1997; Barbé-Tuana et al ., 2020; Tsuji et al ., 2022). Here we extended this concept by showing for the first time that senescent C57BL/6 mice are prone to L. infantum infection compared to young-infected mice.…”